Circulatory disturbances and oxygen deprivation are a major cause of neurodevelopmental impairments in preterm infants. Cerebral intraventricular hemorrhage (IVH) is the most common of these circulatory disturbances and is particularly prevalent among very-low-birth-weight (VLBW) preterm infants. Longitudinal studies indicate that 25 to 50 percent of VLBW children have cognitive deficits and related disturbances when they reach school age and neonates with IVH makes up a disproportionate number of infants with severe neurodevelopmental handicaps. Hypoxia and ischemia are closely associated with the precipitation of an IVH event and may be long-lasting consequences of IVH. The experiments described in this project are designed to examine the effects of neonatal hypoxia and ischemia on the development of cortical connectivity in the rat and human cerebral cortex. These pathological events result in a number of changes in cortical neuron activity and excitability which may in turn perturb the normal maturation of cortical connectivity. The studies in this research project will use independent models of hypoxia and ischemia to determine the impact of these pathological conditions on: 1) the development of appropriate patterns of callosal connectivity in the rat cerebral cortex during the neonatal period; and 2) the proliferation and structure of synaptic contacts in identified areas of the rat cerebral cortex. In addition, we will obtain cortical tissue from VLBW preterm infants with IVH, VLBW preterm infants without a history of circulatory disturbances and term infants to assess the impact of IVH on cortical synaptogenesis. Understanding the effects of IVH and other circulatory disturbances on the normal basis of the long-term cognitive and intellectual impairments associated with very preterm birth.